Method and system for dynamically updating calibration parameters for an analyte sensor

ABSTRACT

Methods and apparatuses including determining a calibration parameter associated with a detected analyte value, calibrating the analyte value based on the calibration parameter, and dynamically updating the calibration parameter are disclosed. Also provided are systems, kits, and computer program products.

BACKGROUND

Analyte, e.g., glucose monitoring systems including continuous anddiscrete monitoring systems generally include a small, lightweightbattery powered and microprocessor controlled system which is configuredto detect signals proportional to the corresponding measured glucoselevels using an electrometer, and RF signals to transmit the collecteddata. One aspect of certain analyte monitoring systems include atranscutaneous or subcutaneous analyte sensor configuration which is,for example, partially mounted on the skin of a subject whose analytelevel is to be monitored. The sensor cell may use a two orthree-electrode (work, reference and counter electrodes) configurationdriven by a controlled potential (potentiostat) analog circuit connectedthrough a contact system.

The analyte sensor may be configured so that a portion thereof is placedunder the skin of the patient so as to detect the analyte levels of thepatient, and another portion of segment of the analyte sensor that is incommunication with the transmitter unit. The transmitter unit isconfigured to transmit the analyte levels detected by the sensor over awireless communication link such as an RF (radio frequency)communication link to a receiver/monitor unit. The receiver/monitor unitperforms data analysis, among others on the received analyte levels togenerate information pertaining to the monitored analyte levels.

To obtain accurate data from the analyte sensor, calibration isnecessary. Typically, blood glucose measurements are periodicallyobtained using, for example, a blood glucose meter, and the measuredblood glucose values are used to calibrate the sensors. Indeed, thepatient must calibrate each new analyte sensor using for example,capillary blood glucose measurements. Due to a lag factor between themonitored data and the measured blood glucose values, an error istypically introduced in the monitored data.

In view of the foregoing, it would be desirable to have a method andsystem for calibrating analyte sensors of an analyte monitoring systemto minimize the lag error and compensation of such lag errors in analytemonitoring systems.

SUMMARY OF THE INVENTION

In one embodiment, a method including determining a calibrationparameter associated with a detected analyte value, calibrating theanalyte value based on the calibration parameter, and dynamicallyupdating the calibration parameter is disclosed.

These and other objects, features and advantages of the presentinvention will become more fully apparent from the following detaileddescription of the embodiments, the appended claims and the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a block diagram of a data monitoring and managementsystem for practicing one or more embodiments of the present invention;

FIG. 2 is a block diagram of the transmitter unit of the data monitoringand management system shown in FIG. 1 in accordance with one embodimentof the present invention;

FIG. 3 is a block diagram of the receiver/monitor unit of the datamonitoring and management system shown in FIG. 1 in accordance with oneembodiment of the present invention;

FIG. 4 is a flowchart illustrating an overall dynamically updatingcalibration in accordance with one embodiment of the present invention;

FIG. 5 is a flowchart illustrating the lag correction and calibrationroutine of the overall dynamically updating calibration shown in FIG. 4in accordance with one embodiment of the present invention;

FIG. 6 is a flowchart illustrating the lag correction and dynamicallyupdating calibration routine of the overall dynamically updatingcalibration shown in FIG. 4 in accordance with one embodiment of thepresent invention;

FIG. 7 illustrates an example of the lag corrected and calibrated sensordata in accordance with one embodiment of the present invention; and

FIG. 8 illustrates a further example of the lag corrected and calibratedsensor data in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION

As described in further detail below, in accordance with the variousembodiments of the present invention, there is provided a method andsystem for calibration of analyte sensors to reduce errors in the sensormeasurements. In particular, within the scope of the present invention,there are provided method and system for calibrating subcutaneous ortranscutaneously positioned analyte sensors to compensate for lag errorsassociated with the estimated sensor sensitivity.

FIG. 1 illustrates a data monitoring and management system such as, forexample, analyte (e.g., glucose) monitoring system 100 in accordancewith one embodiment of the present invention. The subject invention isfurther described primarily with respect to a glucose monitoring systemfor convenience and such description is in no way intended to limit thescope of the invention. It is to be understood that the analytemonitoring system may be configured to monitor a variety of analytes,e.g., lactate, and the like.

Analytes that may be monitored include, for example, acetyl choline,amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase(e.g., CK-MB), creatine, DNA, fructosamine, glucose, glutamine, growthhormones, hormones, ketones, lactate, peroxide, prostate-specificantigen, prothrombin, RNA, thyroid stimulating hormone, and troponin.The concentration of drugs, such as, for example, antibiotics (e.g.,gentamicin, vancomycin, and the like), digitoxin, digoxin, drugs ofabuse, theophylline, and warfarin, may also be monitored.

The analyte monitoring system 100 includes a sensor 101, a transmitterunit 102 coupled to the sensor 101, and a primary receiver unit 104which is configured to communicate with the transmitter unit 102 via acommunication link 103. The primary receiver unit 104 may be furtherconfigured to transmit data to a data processing terminal 105 forevaluating the data received by the primary receiver unit 104. Moreover,the data processing terminal in one embodiment may be configured toreceive data directly from the transmitter unit 102 via a communicationlink 106 which may optionally be configured for bi-directionalcommunication.

Also shown in FIG. 1 is a secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the transmitter unit 102. Moreover, as shown inthe Figure, the secondary receiver unit 106 is configured to communicatewith the primary receiver unit 104 as well as the data processingterminal 105. Indeed, the secondary receiver unit 106 may be configuredfor bi-directional wireless communication with each of the primaryreceiver unit 104 and the data processing terminal 105. As discussed infurther detail below, in one embodiment of the present invention, thesecondary receiver unit 106 may be configured to include a limitednumber of functions and features as compared with the primary receiverunit 104. As such, the secondary receiver unit 106 may be configuredsubstantially in a smaller compact housing or embodied in a device suchas a wrist watch, for example. Alternatively, the secondary receiverunit 106 may be configured with the same or substantially similarfunctionality as the primary receiver unit 104, and may be configured tobe used in conjunction with a docking cradle unit for placement bybedside, for night time monitoring, and/or bi-directional communicationdevice.

Only one sensor 101, transmitter unit 102, communication link 103, anddata processing terminal 105 are shown in the embodiment of the analytemonitoring system 100 illustrated in FIG. 1. However, it will beappreciated by one of ordinary skill in the art that the analytemonitoring system 100 may include one or more sensor 101, transmitterunit 102, communication link 103, and data processing terminal 105.Moreover, within the scope of the present invention, the analytemonitoring system 100 may be a continuous monitoring system, orsemi-continuous, or a discrete monitoring system. In a multi-componentenvironment, each device is configured to be uniquely identified by eachof the other devices in the system so that communication conflict isreadily resolved between the various components within the analytemonitoring system 100.

In one embodiment of the present invention, the sensor 101 is physicallypositioned in or on the body of a user whose analyte level is beingmonitored. The sensor 101 may be configured to continuously sample theanalyte level of the user and convert the sampled analyte level into acorresponding data signal for transmission by the transmitter unit 102.In one embodiment, the transmitter unit 102 is mounted on the sensor 101so that both devices are positioned on the user's body. The transmitterunit 102 performs data processing such as filtering and encoding on datasignals, each of which corresponds to a sampled analyte level of theuser, for transmission to the primary receiver unit 104 via thecommunication link 103.

In one embodiment, the analyte monitoring system 100 is configured as aone-way RF communication path from the transmitter unit 102 to theprimary receiver unit 104. In such embodiment, the transmitter unit 102transmits the sampled data signals received from the sensor 101 withoutacknowledgement from the primary receiver unit 104 that the transmittedsampled data signals have been received. For example, the transmitterunit 102 may be configured to transmit the encoded sampled data signalsat a fixed rate (e.g., at one minute intervals) after the completion ofthe initial power on procedure. Likewise, the primary receiver unit 104may be configured to detect such transmitted encoded sampled datasignals at predetermined time intervals. Alternatively, the analytemonitoring system 100 may be configured with a bi-directional RF (orotherwise) communication between the transmitter unit 102 and theprimary receiver unit 104.

Additionally, in one aspect, the primary receiver unit 104 may includetwo sections. The first section is an analog interface section that isconfigured to communicate with the transmitter unit 102 via thecommunication link 103. In one embodiment, the analog interface sectionmay include an RF receiver and an antenna for receiving and amplifyingthe data signals from the transmitter unit 102, which are thereafter,demodulated with a local oscillator and filtered through a band-passfilter. The second section of the primary receiver unit 104 is a dataprocessing section which is configured to process the data signalsreceived from the transmitter unit 102 such as by performing datadecoding, error detection and correction, data clock generation, anddata bit recovery.

In operation, upon completing the power-on procedure, the primaryreceiver unit 104 is configured to detect the presence of thetransmitter unit 102 within its range based on, for example, thestrength of the detected data signals received from the transmitter unit102 or a predetermined transmitter identification information. Uponsuccessful synchronization with the corresponding transmitter unit 102,the primary receiver unit 104 is configured to begin receiving from thetransmitter unit 102 data signals corresponding to the user's detectedanalyte level. More specifically, the primary receiver unit 104 in oneembodiment is configured to perform synchronized time hopping with thecorresponding synchronized transmitter unit 102 via the communicationlink 103 to obtain the user's detected analyte level.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs)), and the like, each ofwhich may be configured for data communication with the receiver via awired or a wireless connection. Additionally, the data processingterminal 105 may further be connected to a data network (not shown) forstoring, retrieving and updating data corresponding to the detectedanalyte level of the user.

Within the scope of the present invention, the data processing terminal105 may include an infusion device such as an insulin infusion pump orthe like, which may be configured to administer insulin to patients, andwhich may be configured to communicate with the receiver unit 104 forreceiving, among others, the measured analyte level. Alternatively, thereceiver unit 104 may be configured to integrate an infusion devicetherein so that the receiver unit 104 is configured to administerinsulin therapy to patients, for example, for administering andmodifying basal profiles, as well as for determining appropriate bolusesfor administration based on, among others, the detected analyte levelsreceived from the transmitter unit 102.

Additionally, the transmitter unit 102, the primary receiver unit 104and the data processing terminal 105 may each be configured forbi-directional wireless communication such that each of the transmitterunit 102, the primary receiver unit 104 and the data processing terminal105 may be configured to communicate (that is, transmit data to andreceive data from) with each other via the wireless communication link103. More specifically, the data processing terminal 105 may in oneembodiment be configured to receive data directly from the transmitterunit 102 via the communication link 106, where the communication link106, as described above, may be configured for bi-directionalcommunication.

In this embodiment, the data processing terminal 105 which may includean insulin pump, may be configured to receive the analyte signals fromthe transmitter unit 102, and thus, incorporate the functions of thereceiver 103 including data processing for managing the patient'sinsulin therapy and analyte monitoring. In one embodiment, thecommunication link 103 may include one or more of an RF communicationprotocol, an infrared communication protocol, a Bluetooth enabledcommunication protocol, an 802.11x wireless communication protocol, oran equivalent wireless communication protocol which would allow secure,wireless communication of several units (for example, per HIPPArequirements) while avoiding potential data collision and interference.

FIG. 2 is a block diagram of the transmitter of the data monitoring anddetection system shown in FIG. 1 in accordance with one embodiment ofthe present invention. Referring to the Figure, the transmitter unit 102in one embodiment includes an analog interface 201 configured tocommunicate with the sensor 101 (FIG. 1), a user input 202, and atemperature detection section 203, each of which is operatively coupledto a transmitter processor 204 such as a central processing unit (CPU).As can be seen from FIG. 2, there are provided four contacts, three ofwhich are electrodes—work electrode (W) 210, guard contact (G) 211,reference electrode (R) 212, and counter electrode (C) 213, eachoperatively coupled to the analog interface 201 of the transmitter unit102 for connection to the sensor unit 201 (FIG. 1). In one embodiment,each of the work electrode (W) 210, guard contact (G) 211, referenceelectrode (R) 212, and counter electrode (C) 213 may be made using aconductive material that is either printed or etched, for example, suchas carbon which may be printed, or metal foil (e.g., gold) which may beetched.

Further shown in FIG. 2 are a transmitter serial communication section205 and an RF transmitter 206, each of which is also operatively coupledto the transmitter processor 204. Moreover, a power supply 207 such as abattery is also provided in the transmitter unit 102 to provide thenecessary power for the transmitter unit 102. Additionally, as can beseen from the Figure, clock 208 is provided to, among others, supplyreal time information to the transmitter processor 204.

In one embodiment, a unidirectional input path is established from thesensor 101 (FIG. 1) and/or manufacturing and testing equipment to theanalog interface 201 of the transmitter unit 102, while a unidirectionaloutput is established from the output of the RF transmitter 206 of thetransmitter unit 102 for transmission to the primary receiver unit 104.In this manner, a data path is shown in FIG. 2 between theaforementioned unidirectional input and output via a dedicated link 209from the analog interface 201 to serial communication section 205,thereafter to the processor 204, and then to the RF transmitter 206. Assuch, in one embodiment, via the data path described above, thetransmitter unit 102 is configured to transmit to the primary receiverunit 104 (FIG. 1), via the communication link 103 (FIG. 1), processedand encoded data signals received from the sensor 101 (FIG. 1).Additionally, the unidirectional communication data path between theanalog interface 201 and the RF transmitter 206 discussed above allowsfor the configuration of the transmitter unit 102 for operation uponcompletion of the manufacturing process as well as for directcommunication for diagnostic and testing purposes.

As discussed above, the transmitter processor 204 is configured totransmit control signals to the various sections of the transmitter unit102 during the operation of the transmitter unit 102. In one embodiment,the transmitter processor 204 also includes a memory (not shown) forstoring data such as the identification information for the transmitterunit 102, as well as the data signals received from the sensor 101. Thestored information may be retrieved and processed for transmission tothe primary receiver unit 104 under the control of the transmitterprocessor 204. Furthermore, the power supply 207 may include acommercially available battery.

The transmitter unit 102 is also configured such that the power supplysection 207 is capable of providing power to the transmitter for aminimum of about three months of continuous operation after having beenstored for about eighteen months in a low-power (non-operating) mode. Inone embodiment, this may be achieved by the transmitter processor 204operating in low power modes in the non-operating state, for example,drawing no more than approximately 1 μA of current. Indeed, in oneembodiment, the final step during the manufacturing process of thetransmitter unit 102 may place the transmitter unit 102 in the lowerpower, non-operating state (i.e., post-manufacture sleep mode). In thismanner, the shelf life of the transmitter unit 102 may be significantlyimproved. Moreover, as shown in FIG. 2, while the power supply unit 207is shown as coupled to the processor 204, and as such, the processor 204is configured to provide control of the power supply unit 207, it shouldbe noted that within the scope of the present invention, the powersupply unit 207 is configured to provide the necessary power to each ofthe components of the transmitter unit 102 shown in FIG. 2.

Referring back to FIG. 2, the power supply section 207 of thetransmitter unit 102 in one embodiment may include a rechargeablebattery unit that may be recharged by a separate power supply rechargingunit (for example, provided in the receiver unit 104) so that thetransmitter unit 102 may be powered for a longer period of usage time.Moreover, in one embodiment, the transmitter unit 102 may be configuredwithout a battery in the power supply section 207, in which case thetransmitter unit 102 may be configured to receive power from an externalpower supply source (for example, a battery) as discussed in furtherdetail below.

Referring yet again to FIG. 2, the temperature detection section 203 ofthe transmitter unit 102 is configured to monitor the temperature of theskin near the sensor insertion site. The temperature reading is used toadjust the analyte readings obtained from the analog interface 201. TheRF transmitter 206 of the transmitter unit 102 may be configured foroperation in the frequency band of 315 MHz to 322 MHz, for example, inthe United States. Further, in one embodiment, the RF transmitter 206 isconfigured to modulate the carrier frequency by performing FrequencyShift Keying and Manchester encoding. In one embodiment, the datatransmission rate is 19,200 symbols per second, with a minimumtransmission range for communication with the primary receiver unit 104.

Referring yet again to FIG. 2, also shown is a leak detection circuit214 coupled to the guard electrode (G) 211 and the processor 204 in thetransmitter unit 102 of the data monitoring and management system 100.The leak detection circuit 214 in accordance with one embodiment of thepresent invention may be configured to detect leakage current in thesensor 101 to determine whether the measured sensor data are corrupt orwhether the measured data from the sensor 101 is accurate.

Additional detailed description of the continuous analyte monitoringsystem, its various components including the functional descriptions ofthe transmitter are provided in U.S. Pat. No. 6,175,752 issued Jan. 16,2001 entitled “Analyte Monitoring Device and Methods of Use”, and inapplication Ser. No. 10/745,878 filed Dec. 26, 2003 entitled “ContinuousGlucose Monitoring System and Methods of Use”, each assigned to theAssignee of the present application.

FIG. 3 is a block diagram of the receiver/monitor unit of the datamonitoring and management system shown in FIG. 1 in accordance with oneembodiment of the present invention. Referring to FIG. 3, the primaryreceiver unit 104 includes a blood glucose test strip interface 301, anRF receiver 302, an input 303, a temperature detection section 304, anda clock 305, each of which is operatively coupled to a receiverprocessor 307. As can be further seen from the Figure, the primaryreceiver unit 104 also includes a power supply 306 operatively coupledto a power conversion and monitoring section 308. Further, the powerconversion and monitoring section 308 is also coupled to the receiverprocessor 307. Moreover, also shown are a receiver serial communicationsection 309, and an output 310, each operatively coupled to the receiverprocessor 307.

In one embodiment, the test strip interface 301 includes a glucose leveltesting portion to receive a manual insertion of a glucose test strip,and thereby determine and display the glucose level of the test strip onthe output 310 of the primary receiver unit 104. This manual testing ofglucose can be used to calibrate sensor 101. The RF receiver 302 isconfigured to communicate, via the communication link 103 (FIG. 1) withthe RF transmitter 206 of the transmitter unit 102, to receive encodeddata signals from the transmitter unit 102 for, among others, signalmixing, demodulation, and other data processing. The input 303 of theprimary receiver unit 104 is configured to allow the user to enterinformation into the primary receiver unit 104 as needed. In one aspect,the input 303 may include one or more keys of a keypad, atouch-sensitive screen, or a voice-activated input command unit. Thetemperature detection section 304 is configured to provide temperatureinformation of the primary receiver unit 104 to the receiver processor307, while the clock 305 provides, among others, real time informationto the receiver processor 307.

Each of the various components of the primary receiver unit 104 shown inFIG. 3 is powered by the power supply 306 which, in one embodiment,includes a battery. Furthermore, the power conversion and monitoringsection 308 is configured to monitor the power usage by the variouscomponents in the primary receiver unit 104 for effective powermanagement and to alert the user, for example, in the event of powerusage which renders the primary receiver unit 104 in sub-optimaloperating conditions. An example of such sub-optimal operating conditionmay include, for example, operating the vibration output mode (asdiscussed below) for a period of time thus substantially draining thepower supply 306 while the processor 307 (thus, the primary receiverunit 104) is turned on. Moreover, the power conversion and monitoringsection 308 may additionally be configured to include a reverse polarityprotection circuit such as a field effect transistor (FET) configured asa battery activated switch.

The serial communication section 309 in the primary receiver unit 104 isconfigured to provide a bi-directional communication path from thetesting and/or manufacturing equipment for, among others,initialization, testing, and configuration of the primary receiver unit104. Serial communication section 104 can also be used to upload data toa computer, such as time-stamped blood glucose data. The communicationlink with an external device (not shown) can be made, for example, bycable, infrared (IR) or RF link. The output 310 of the primary receiverunit 104 is configured to provide, among others, a graphical userinterface (GUI) such as a liquid crystal display (LCD) for displayinginformation. Additionally, the output 310 may also include an integratedspeaker for outputting audible signals as well as to provide vibrationoutput as commonly found in handheld electronic devices, such as mobiletelephones presently available. In a further embodiment, the primaryreceiver unit 104 also includes an electro-luminescent lamp configuredto provide backlighting to the output 310 for output visual display indark ambient surroundings.

Referring back to FIG. 3, the primary receiver unit 104 in oneembodiment may also include a storage section such as a programmable,non-volatile memory device as part of the processor 307, or providedseparately in the primary receiver unit 104, operatively coupled to theprocessor 307. The processor 307 is further configured to performManchester decoding as well as error detection and correction upon theencoded data signals received from the transmitter unit 102 via thecommunication link 103.

FIG. 4 is a flowchart illustrating an overall dynamically updatingcalibration in accordance with one embodiment of the present invention.Referring to FIG. 4, a counter such as a calibration counter istriggered to perform calibration of the monitored data such as theanalyte data received from the transmitter unit 102 (FIG. 1). In oneembodiment, the calibration counter may include a timer or a clock whichmay be configured to prompt the user or the patient to initiate theacquisition of reference data at a predetermined time intervals. Whenthe calibration counter is initially triggered, the time counter T isinitialized to zero (0). Thereafter, a calibration parameter isdetermined based on, for example, the acquired reference data and themonitored sensor data at time T=0. Moreover, in one embodiment, themonitored sensor data may be updated based on the calibration parameter.In one embodiment, the calibration parameter may include a sensorsensitivity value associated with the analyte sensor 101 (FIG. 1)configured to monitor the analyte levels of the patient.

As described in further detail below, for example, in conjunction withFIG. 5, in particular embodiments, during the initial calibration stageat T=0, a reference glucose value is determined, for example, such as acapillary blood glucose value using a blood glucose meter such asFREESTYLE® meter or PRECISION XTRA™ meter available from Abbott DiabetesCare Inc., Alameda, Calif. In addition, the monitored sensor data at ornear the calibration time (T=0) is retrieved which may include themonitored sensor data at time T=T−1, at time T=T+1, or any othersuitable time period (for example, from the processing and storage unit307 (FIG. 3) of the receiver unit 104 (FIG. 1).

More specifically, in one embodiment, the monitored sensor data at thecalibration time (T=0) may include one or more monitored sensor data inaddition to the monitored sensor data point at the calibration time(T=0). That is, in one embodiment, the monitored sensor data at thecalibration time (T=0) may include all monitored sensor data availablefor retrieval from the receiver unit 104 (FIG. 1) at the calibrationtime (T=0). For example, to reduce the contribution of noise in themeasured sensor data, an average of the two most recent sensor data maybe associated with the monitored sensor data at the calibration time(T=0).

Broadly, within the scope of the present disclosure, the monitoredsensor data at a predetermined time may include, in particularembodiments, an estimate of the sensor data at the predetermined time asdetermined by the one or more filters which may be configured to use themonitored sensor data up to and including the data point at thepredetermined time (for example, up to the data point at calibrationtime (T=0)). In one embodiment, one or more filters such as a finiteimpulse response (FIR) filter may be used to determine the best estimateat a predetermined time using a finite window of monitored sensor dataup to the current or most recent monitored sensor data point.

Referring back to FIG. 4, after determining the calibration parameterand updating the monitored data at the calibration time (T=0), thecounter is incremented by one (1), and dynamic, real-time update of thecalibration parameter is performed. In one embodiment, the counter maybe configured to increment by one with each reception of sensor datafrom the transmitter unit 102 (FIG. 1). After dynamically updating thecalibration parameter at the subsequent incremented time (T=1), it isdetermined whether the counter has reached a predetermined count (forexample, set at seven (7)). If it is determined that the counter has notreached the predetermined count, then the routine in one embodimentreturns to step 430 where the counter is incremented by one (1) and thedynamically updating calibration parameter and monitored sensor data isperformed for monitored data at the second subsequent incremented time(T=2).

On the other hand, if it is determined that the counter has reached thepredetermined count, then in one embodiment, subsequent monitored sensordata may be updated based on the dynamically updated calibrationparameter and/or updated monitored sensor data. Thereafter, inparticular embodiments, it is determined whether further or subsequentlag correction will likely not yield more accurate monitored data value(or with less errors). Therefore, in one embodiment, the routineterminates and awaits for the subsequent calibration time, for example,to repeat the processes described above in conjunction with FIG. 4.

In this manner, within the scope of the present disclosure, there areprovided methods and system for dynamically, and in particularembodiments, in real-time, obtaining reference data at a firstpredetermined time, receiving measured data prior to and including (ornear) the first predetermined time, calculating a first calibrationparameter (or parameters) using the data, calibrating the measured databased on the calibration parameter, receiving measured data at a secondpredetermined time, updating the calibration parameter based on all ofthe previous data and the newly received measured data, calibrating thenewly received measured data based on the updated calibration parameter,and repeating a number of time the process of receiving new measurementdata, updating the calibration parameter, calibrating the newly receivedmeasurement data, and calibrating any newly received measurement datawith the fully updated calibration parameter.

A method in a further embodiment may include performing lag compensationon the measured data that is used to update the calibration parameter.Lag compensation may optionally be performed on the measured data thatis calibrated. A method in a further embodiment includes filtering themeasured data that is used to update the calibration parameter.

FIG. 5 is a flowchart illustrating the lag correction and calibrationroutine of the overall dynamically updating calibration shown in FIG. 4in accordance with one embodiment of the present invention. Referring toFIG. 5, the determination of calibration parameter and updating themonitored analyte level at the calibration time (T=0) is described infurther detail. More specifically, in one embodiment, a capillary bloodglucose value is determined at the calibration time (T=0), and themonitored analyte value at the calibration time is retrieved from thereceiver unit 104 of the monitoring system 100 (FIG. 1).

Thereafter, a rate of change of the monitored data at the calibrationtime (T=0) is determined. In one embodiment, the rate of change of themonitored data at the calibration time (T=0) may be determined using oneor more filters including, but not limited to infinite impulse response(IIR) filter, finite impulse response (FIR) filter, backward and/orforward smoothing techniques (e.g., Kalman filtering technique), or anyother equivalent one or more causal filters that balance signal noisereduction with lag correction.

Upon determining the rate of change of the monitored data at thecalibration time (T=0), the monitored data at the calibration time (T=0)is updated. In one embodiment, the updated monitored sensor data mayinclude lag corrected monitored data at the calibration time (T=0).Optionally, the lag correction for the monitored data at the calibrationtime (T=0) may be skipped and not performed. In one embodiment, the lagcorrected monitored data at the calibration time (T=0) may be determinedby applying the determined rate of change of the monitored data at thecalibration time (T=0) to a predetermined constant value. In oneembodiment, the predetermined constant value may include, apredetermined time constant.

For example, in one embodiment, the predetermined time constant mayinclude a fixed time constant in the range of approximately four tofifteen minutes, and which may be associated with the one or more of thepatient physiological profile, one or more attributes associated withthe monitoring system 100 (including, for example but not limited to,the characteristics of the analyte sensor 101). In a further aspect, thepredetermined time constant may vary based on one or more factorsincluding, for example, but not limited to the timing and amount of foodintake by the patient, exogenous insulin intake, physical activities bythe patient such as exercise, or any other factors that may affect thetime constant, and which may be empirically determined.

Referring again to FIG. 5, the calibration parameter (for example, thesensitivity of the analyte sensor 101 FIG. 1), may be determined forexample, in one embodiment, by determining the ratio of the monitoreddata (optionally lag corrected) at the calibration time (T=0) and thereference data obtained using, for example, the blood glucose meter asdescribed above. In one embodiment, the calibration parameter may bedetermined by dividing the monitored data at the calibration time (T=0)by the reference data such as the capillary blood glucose value at thecalibration time (T=0).

Thereafter, in one embodiment, the calibrated and updated monitoredsensor data at the calibration time (T=0) is determined based upon themonitored data (optionally lag corrected) and the calibration parameteras determined above. For example, in one embodiment, the calibrated andupdated monitored sensor data at the calibration time (T=0) may bedetermined by dividing the lag corrected monitored data at calibrationtime (T=0) by the determined calibration parameter.

FIG. 6 is a flowchart illustrating the lag correction and dynamicallyupdating calibration routine of the overall dynamically updatingcalibration shown in FIG. 4 in accordance with one embodiment of thepresent invention. Referring to FIGS. 4 and 6, with the counterincremented by one (see step 430 of FIG. 4), the analyte value at thesubsequent incremented time (T=1) is retrieved from, for example, theprocessing and storage unit 307 (FIG. 3) of the receiver unit 104. Inparticular, in one embodiment, the rate of change of the monitored dataat the calibration time (T=0) is updated based on the monitored datavalue at the subsequent incremented time (T=1). In other words, with themonitored data values at calibration time (T=0) and prior data and atthe subsequent incremented time (T=1), the rate of change of themonitored data at the calibration time (T=0) may be estimated with animproved accuracy. Again, in one embodiment, the rate of change may bedetermined based on one or more not limited to infinite impulse response(IIR) filter, finite impulse response (FIR) filter, backward and/orforward smoothing techniques (e.g., Kalman filtering technique), or anyother equivalent filtering or smoothing techniques.

With the updated rate of change at the calibration time (T=0)determined, monitored data (optionally lag corrected) at calibrationtime (T=0) is updated. That is, in one embodiment, the lag correctedsensor data at the calibration time (T=0) is updated based on the priorlag corrected and calibrated data at calibration time (T=0), and inconjunction with the predetermined constant (for example, thepredetermined time constant discussed above), and the updated rate ofchange of the monitored data at the calibration time (T=0). For example,in one embodiment, the lag corrected monitored data at the calibrationtime (T=0) is updated or determined by taking the sum of the lagcorrected and calibration sensor value at calibration time (T=0) asdetermined above, with the updated rate of change of monitored data atcalibration time (T=0) multiplied by the predetermined constant. Inother words, in one embodiment, the updated rate of change of themonitored data at calibration time (T=0) may be multiplied by thepredetermined constant, and thereafter, the resulting value is added tothe lag corrected and calibrated monitored data at the calibration time(T=0) previously determined (see for example, step 420).

Referring again to FIG. 6, after determining the updated lag correctedmonitored data at calibration time (T=0) based on monitored data at thesubsequent incremented time (T=1) as described above, in one embodiment,the calibration parameter (for example, the sensitivity of the sensor101 (FIG. 1) is updated based on the updated lag corrected monitoreddata at calibration time (T=0) described above. In particular, in oneembodiment, the calibration parameter may be updated by determining theratio of the updated lag corrected monitored data at calibration time(T=0) and the reference value (for example, the capillary blood glucosevalue) determined at calibration time (T=0).

After updating the calibration parameter as described above, in oneembodiment, the lag corrected and calibrated monitored data at thesubsequent incremented time (T=1) is determined based on the updatedcalibration parameter value. For example, in one embodiment, themonitored sensor data at the subsequent incremented time (T=1) in oneembodiment may be divided by the updated sensitivity to determine thedynamically lag corrected and calibrated monitored sensor data at thesubsequent incremented time (T=1).

In another embodiment, the dynamically lag corrected and calibratedmonitored sensor data at the subsequent incremented time (T=1) may bedetermined based on the updated calibration parameter and thedynamically lag corrected monitored sensor data at the subsequentincremented time (T=1). In this case, the dynamically updated sensordata at the subsequent incremented time (T=1) in one embodiment may bedetermined by calculating the rate of change of the monitored data atthe subsequent incremented time (T=1) using similar filtering techniquesas described above, and applying the predetermined constant (forexample, the predetermined time constant discussed above), the result ofwhich is then added to the detected or monitored data at the subsequentincremented time (T=1). In other words, in one embodiment, thecalculated rate of change of the monitored data at the subsequentincremented time (T=1) is multiplied by the predetermined time constant,and the resulting value is added to the monitored data value at thesubsequent incremented time (T=1). This sum in one embodiment representsthe dynamically updated monitored sensor data at the subsequentincremented time (T=1).

In this manner, in one embodiment, lag correction of analyte sensor datamay be pseudo-retrospectively (or substantially in real time) updatedusing the monitored analyte data stream substantially continuouslydetected by the sensor 101 (FIG. 1) with the dynamic updating of thecalibration parameter. Thus, in one aspect, lag error or error due tolag compensation may be overcome by, for example, updating the sensorsensitivity retrospectively with each value of the detected or monitoredanalyte levels. Accordingly, in one embodiment, calibration inaccuraciesdue to change (for example, rapid acceleration) of analyte levels afterperforming discrete calibration may be mitigated by updating thecalibration routine taking into consideration the near immediate postcalibration analyte sensor data to obtain a more reliable and accuratevalue associated with the rate of change of the monitored analytelevels. In one embodiment, the overall system accuracy of the monitoredand detected analyte values may be improved.

FIG. 7 illustrates an example of the lag corrected and calibrated sensordata in accordance with one embodiment of the present invention.Referring to FIG. 7, a comparison illustrating the improvement incalibration in the dynamically updated (for example,pseudo-retrospectively performed) lag correction approach in accordancewith one embodiment is shown. Referring to FIG. 7, the reference datapoints (associated with the capillary blood glucose values) are shown asdata points associated with legend (A), the no lag corrected monitoredsensor data points are associated with legend (B), the lag correctedmonitored sensor data points are associated with legend (C), and thedynamically updated monitored sensor data points are associated withlegend (D).

Referring to FIG. 7, more specifically, when calibrating during a highrate of change (for example, between the 3^(rd) and 4^(th) hour in theFigure), and with uncorrected lag effects, an error in the sensitivityestimate is introduced. For the “No Lag Correction” trace (B), when thehigh rate of change subsides, it can be seen that the estimated glucosevalue is substantially overestimated compared to the reference values.When real time lag correction is introduced, it can be seen that the“Real Time Lag Correction” trace (C) is much closer to the referencevalues, but this is still a substantial overestimation, primarily whenthe glucose rate of change is negative (calibration occurred when therate of change was positive). With the dynamic or pseudo-retrospectivelag correction in accordance with one embodiment, it can be seen thatthe data values (shown with trace associated with legend (D)) match thereference values more accurately.

FIG. 8 illustrates a further example of the lag corrected and calibratedsensor data in accordance with one embodiment of the present invention.Referring to FIG. 8, it can be seen that calibration occurs when theglucose rate-of-change is close to zero. Moreover, the real time lagcorrection signal is shown with a large error when the monitored glucoselevel is fluctuating, contrasted with the trace or curve associated withthe pseudo-retrospective lag correction which, as can be seen from FIG.8 substantially tracks the reference glucose values (e.g., measured fromthe capillary blood). Furthermore, it can be seen that in this example,the trace associated with no lag correction is substantially identicalto the trace or curve associated with the pseudo-retrospective lagcorrection. This may result when the monitored analyte level is notchanging during calibration, and thus there may be no lag error tocorrect, and which is factored in the approaches described in accordancewith the various embodiments described herein.

Referring yet again to FIG. 8, it can be also seen that in certaincases, the real time lag correction may result in further distortion ormore pronounced error factors as compared with the case where no lagcorrection is performed. Accordingly, in one embodiment, it can be seenfrom FIG. 8 that the pseudo-retrospective lag correction in accordancewith the dynamically updating the calibration parameter and themonitored sensor data provides further accuracy and compensation ofpossible additional errors in the monitored sensor data. This can beseen by comparing the portions of the traces shown in FIG. 8 during the11^(th) and the 12^(th) hours, where a rapid change in the monitoredglucose values as a function of time adversely impacts the accuracy ofthe monitored data with real time lag correction (without thepseudo-retrospective lag correction including dynamically updatedcalibration parameter.

Referring to the Figures above, in particular embodiments, thepseudo-retrospective lag correction and calibration and updating ofmonitored sensor data may be performed by one or more processing unitsof the one or more receiver unit (104, 105) the transmitter unit 102 orthe data processing terminal/infusion section 105. In addition, the oneor more of the transmitter unit 102, the primary receiver unit 104,secondary receiver unit 105, or the data processing terminal/infusionsection 105 may also incorporate a blood glucose meter functionality,such that, the housing of the respective one or more of the transmitterunit 102, the primary receiver unit 104, secondary receiver unit 105, orthe data processing terminal/infusion section 105 may include a teststrip port configured to receive a blood sample for determining one ormore blood glucose levels of the patient.

In a further embodiment, the one or more of the transmitter unit 102,the primary receiver unit 104, secondary receiver unit 105, or the dataprocessing terminal/infusion section 105 may be configured to receivethe blood glucose value wirelessly over a communication link from, forexample, a glucose meter. In still a further embodiment, the user orpatient manipulating or using the analyte monitoring system 100 (FIG. 1)may manually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, and the like) incorporatedin the one or more of the transmitter unit 102, the primary receiverunit 104, secondary receiver unit 105, or the data processingterminal/infusion section 105.

A method in accordance with one embodiment of the present inventionincludes obtaining a reference data point at a first predetermined time,receiving a first data at the first predetermined time, calibrating thefirst data based on the reference data point, receiving a second data ata second predetermined time, updating the calibrated first data based onthe second data, and calibrating the second data.

The reference data point may include a blood glucose value.

The first predetermined time may include a calibration time associatedwith the calibration of one or more of the first data or the seconddata.

The first data and the second data may include a respective one of amonitored analyte value.

In one embodiment, calibrating the first data may include determining afirst rate of change of the first data at the first predetermined time,and performing a first lag compensation of the first data based on thefirst rate of change to generate a first lag compensated first data. Ina further embodiment, calibrating the first data may include determininga first calibration parameter associated with the first data based onthe reference data point and the first lag compensated first data, andgenerating a calibrated first data based on the first calibrationparameter and the first lag compensated first data.

Updating the calibrated first data in one embodiment may includedetermining a second rate of change of the first data at the firstpredetermined time based on the second data, and performing a second lagcompensation of the first data based on the second rate of change of thefirst data to generate a second lag compensated first data.

Also, calibrating the second data may include determining a secondcalibration parameter associated with the first data based on thereference data point and the second lag compensated first data, andgenerating a calibrated second data based on the second calibrationparameter and the second lag compensated first data.

A method in accordance with another embodiment may include determining acalibration parameter associated with a detected analyte value,calibrating the analyte value based on the calibration parameter, anddynamically updating the calibration parameter.

The method in another aspect may include calibrating a second detectedanalyte value based on the dynamically updated calibration parameter.

Further, dynamically updating the calibration parameter may also includedetermining a rate of change of the detected analyte value, andgenerating a lag compensated analyte value based on the rate of change.

In addition, calibrating the analyte value may further includedetermining a sensitivity associated with the detected analyte value,and applying the sensitivity to the lag compensated analyte value.

Moreover, in still another embodiment, dynamically updating thecalibration parameter may include updating the rate of change of thedetected analyte value, and updating the lag compensated analyte value,where updating the rate of change may include determining the rate ofchange of the detected analyte value between a first predetermined timeand a second predetermined time.

In still another embodiment, calibrating the analyte value may includedetecting a calibration data, determining a sensitivity based on thecalibration data and the lag compensated analyte value, and generating alag compensated and calibrated analyte value.

An apparatus in accordance with another embodiment may include one ormore processing units, and a memory for storing instructions which, whenexecuted by the one or more processors, causes the one or moreprocessing units to obtain a reference data point at a firstpredetermined time, receive a first data at the first predeterminedtime, calibrate the first data based on the reference data point;receive a second data at a second predetermined time; update thecalibrated first data based on the second data; and calibrate the seconddata.

The memory in another aspect may be configured for storing instructionswhich, when executed by the one or more processing units, causes the oneor more processing units to determine a first rate of change of thefirst data at the first predetermined time, and to perform a first lagcompensation of the first data based on the first rate of change togenerate a first lag compensated first data.

Moreover, the memory in yet another embodiment may be further configuredfor storing instructions which, when executed by the one or moreprocessing units, causes the one or more processing units to determine afirst calibration parameter associated with the first data based on thereference data point and the first lag compensated first data and togenerate a calibrated first data based on the first calibrationparameter and the first lag compensated first data.

Additionally, the memory may still be further configured for storinginstructions which, when executed by the one or more processing units,causes the one or more processing units to determine a second rate ofchange of the first data at the first predetermined time based on thesecond data, and to perform a second lag compensation of the first databased on the second rate of change of the first data to generate asecond lag compensated first data.

In yet still another aspect, the memory may be further configured forstoring instructions which, when executed by the one or more processingunits, causes the one or more processing units to determine a secondcalibration parameter associated with the first data based on thereference data point and the second lag compensated first data, and togenerate a calibrated second data based on the second calibrationparameter and the second lag compensated first data.

A method in accordance with still another embodiment of the presentinvention includes, dynamically, and in particular embodiments, inreal-time, obtaining reference data at a first predetermined time,receiving measured data prior to and including (or near) the firstpredetermined time, calculating a first calibration parameter (orparameters) using the data, calibrating the measured data based on thecalibration parameter, receiving measured data at a second predeterminedtime, updating the calibration parameter based on all of the previousdata and the newly received measured data, calibrating the newlyreceived measured data based on the updated calibration parameter, andrepeating a number of time the process of receiving new measurementdata, updating the calibration parameter, calibrating the newly receivedmeasurement data, and calibrating any newly received measurement datawith the fully updated calibration parameter.

A method in a further embodiment includes performing lag compensation onthe measured data that is used to update the calibration parameter. Lagcompensation may optionally be performed on the measured data that iscalibrated. A method in a further embodiment includes filtering themeasured data that is used to update the calibration parameter.

An apparatus in accordance with yet still another embodiment includesone or more processing units, and a memory for storing instructionswhich, when executed by the one or more processors, causes the one ormore processing units to dynamically, and in particular embodiments, inreal-time, obtain reference data at a first predetermined time, retrievemeasured data prior to and including (or near) the first predeterminedtime, calculate a first calibration parameter (or parameters) using thedata, calibrate the measured data based on the calibration parameter,retrieve measured data at a second predetermined time, update thecalibration parameter based on all of the previous data and the newlyreceived measured data, calibrate the newly received measured data basedon the updated calibration parameter, and repeat a number of time theprocess of receiving new measurement data, updating the calibrationparameter, calibrating the newly received measurement data, andcalibrating any newly received measurement data with the fully updatedcalibration parameter.

Various other modifications and alterations in the structure and methodof operation of this invention will be apparent to those skilled in theart without departing from the scope and spirit of the invention.Although the invention has been described in connection with specificpreferred embodiments, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments. It isintended that the following claims define the scope of the presentinvention and that structures and methods within the scope of theseclaims and their equivalents be covered thereby.

1. A computer implemented method, comprising: obtaining a reference datapoint at a first predetermined time determined based on an analytesample from an in vitro test strip; receiving a first data at the firstpredetermined time from an analyte sensor in fluid contact with aninterstitial fluid; calibrating the first data based on the referencedata point using a processor; receiving a second data at a secondpredetermined time from the analyte sensor; updating the calibratedfirst data based on the second data; and calibrating the second data. 2.The method of claim 1 wherein the reference data point includes a bloodglucose value.
 3. The method of claim 1 wherein the first predeterminedtime includes a calibration time associated with the calibration of oneor more of the first data or the second data.
 4. The method of claim 1wherein the first data and the second data includes a respective one ofa monitored analyte value.
 5. The method of claim 1 wherein calibratingthe first data includes: determining a first rate of change of the firstdata at the first predetermined time; and performing a first lagcompensation of the first data based on the first rate of change togenerate a first lag compensated first data.
 6. The method of claim 5wherein calibrating the first data further includes: determining a firstcalibration parameter associated with the first data based on thereference data point and the first lag compensated first data; andgenerating a calibrated first data based on the first calibrationparameter and the first lag compensated first data.
 7. The method ofclaim 5 wherein updating the calibrated first data includes: determininga second rate of change of the first data at the first predeterminedtime based on the second data; and performing a second lag compensationof the first data based on the second rate of change of the first datato generate a second lag compensated first data.
 8. The method of claim7 wherein calibrating the second data includes: determining a secondcalibration parameter associated with the first data based on thereference data point and the second lag compensated first data; andgenerating a calibrated second data based on the second calibrationparameter and the second lag compensated first data.
 9. A computerimplemented method, comprising: determining a calibration parameterassociated with a detected analyte value based from an analyte sensor influid contact with an interstitial fluid; calibrating the analyte valuebased on the calibration parameter to generate a calibrated analytevalue using a processor; and dynamically updating the calibrationparameter including updating the calibrated analyte value.
 10. Themethod of claim 9 further including calibrating a second detectedanalyte value based on the dynamically updated calibration parameter.11. The method of claim 9 wherein dynamically updating the calibrationparameter includes: determining a rate of change of the detected analytevalue; and generating a lag compensated analyte value based on the rateof change.
 12. The method of claim 9 wherein calibrating the analytevalue includes: determining a sensitivity associated with the detectedanalyte value; and applying the sensitivity to the lag compensatedanalyte value.
 13. The method of claim 11 wherein dynamically updatingthe calibration parameter includes: updating the rate of change of thedetected analyte value; and updating the lag compensated analyte value.14. The method of claim 13 wherein updating the rate of change includesdetermining the rate of change of the detected analyte value between afirst predetermined time and a second predetermined time.
 15. The methodof claim 11 wherein calibrating the analyte value includes: detecting acalibration data; determining a sensitivity based on the calibrationdata and the lag compensated analyte value; and generating a lagcompensated and calibrated analyte value.
 16. The method of claim 15wherein the calibration data includes a blood glucose value.
 17. Anapparatus, comprising: one or more processing units; and a memory forstoring instructions which, when executed by the one or more processors,causes the one or more processing units to obtain a reference data pointat a first predetermined time, receive a first data from an analytesensor at the first predetermined time, calibrate the first data basedon the reference data point; receive a second data from an analytesensor at a second predetermined time; update the calibrated first databased on the second data; and calibrate the second data.
 18. Theapparatus of claim 17 wherein the reference data point includes a bloodglucose value.
 19. The apparatus of claim 17 wherein the firstpredetermined time includes a calibration time associated with thecalibration of one or more of the first data or the second data.
 20. Theapparatus of claim 17 wherein the first data and the second dataincludes a respective one of a monitored analyte value.
 21. Theapparatus of claim 17 wherein the memory is further configured forstoring instructions which, when executed by the one or more processingunits, causes the one or more processing units to determine a first rateof change of the first data at the first predetermined time, and toperform a first lag compensation of the first data based on the firstrate of change to generate a first lag compensated first data.
 22. Theapparatus of claim 21 wherein the memory is further configured forstoring instructions which, when executed by the one or more processingunits, causes the one or more processing units to determine a firstcalibration parameter associated with the first data based on thereference data point and the first lag compensated first data and togenerate a calibrated first data based on the first calibrationparameter and the first lag compensated first data.
 23. The apparatus ofclaim 21 wherein the memory is further configured for storinginstructions which, when executed by the one or more processing units,causes the one or more processing units to determine a second rate ofchange of the first data at the first predetermined time based on thesecond data, and to perform a second lag compensation of the first databased on the second rate of change of the first data to generate asecond lag compensated first data.
 24. The apparatus of claim 23 whereinthe memory is further configured for storing instructions which, whenexecuted by the one or more processing units, causes the one or moreprocessing units to determine a second calibration parameter associatedwith the first data based on the reference data point and the second lagcompensated first data, and to generate a calibrated second data basedon the second calibration parameter and the second lag compensated firstdata.